Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

• Published in: Cancer chemotherapy and pharmacology 2016-08, Vol.78 (2), p.377-382
• Main Authors: Mizoguchi, Kosuke, Nakamura, Yoichi, Sano, Kazumi, Sato, Shuntaro, Ikegami, Yoji, Motoshima, Kohei, Takemoto, Shinnosuke, Ogawara, Daiki, Senju, Hiroaki, Sugasaki, Nanae, Ikeda, Takaya, Yamaguchi, Hiroyuki, Nakatomi, Katsumi, Fukuda, Minoru, Izumikawa, Koichi, Mukae, Hiroshi
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Chromatography, High Pressure Liquid - methods; Disease-Free Survival; Female; Half-Life; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; Oncology; Original Article; Pharmacology/Toxicology; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Receptor, Epidermal Growth Factor - genetics; Survival Rate
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3097-4

Purpose The relationship between plasma concentration and antitumor activity of gefitinib was assessed in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR ) mutations. Patients and methods Plasma trough levels of gefitinib were measured on days 2 (D2) and 8 (D8) by high-performance liquid chromatography in 31 patients. Plasma concentrations of gefitinib were also measured 10 h after the first administration in 21 of these patients to calculate the elimination half-life of gefitinib. Results The median trough levels were: 197 ng/ml 10 h from the first administration of gefitinib; 113 ng/ml on D2; and 358 ng/ml on D8. The median D8/D2 ratio was 2.709, and the median elimination half-life was 15.7 h. The median progression-free survival (PFS) was 273 days, and the median overall survival (OS) was 933 days. A high D8/D2 ratio was significantly correlated with better PFS, though the plasma trough levels on D2 and D8 were not significantly related to PFS. The elimination half-life was not a significant factor for PFS, but it was significantly correlated with high-grade adverse events. Pharmacokinetic parameters were not significantly correlated with OS. Conclusions A high D8/D2 ratio, but not elimination half-life, might be a predictor of better PFS in patients with NSCLC harboring EGFR mutations treated with gefitinib. On the other hand, long elimination half-life was related to high-grade adverse events in these patients. Clinical Trial Registration UMIN000001066.